DE1543273C3 - 7 alpha-methyl-delta to the power of 5 (16) -steroids of the oestran series and process for their production - Google Patents

Description

-R,

R ₁ O

wherein R is an oxygen atom or the group OX (aY), in which X is a hydrogen atom or a phenylpropionyl radical and Y a hydrogen atom or a methyl, ethyl, vinyl or ethynyl radical is.

2. zl ^{5 (10)} - 3 - keto - Ία - methyl -17/3 - hydroxy-17a-ethinyl-estrene.

3. A method for the preparation of compounds according to claim 1, characterized in that one is a compound of the general formula

R ₁ O

wherein R _{1 is} a hydrocarbon _{radical, R 2 is} a hydrogen atom or an acyl radical, R _{3 is} a hydrogen atom, a lower alkyl radical or a lower alkenyl radical, in a manner known per se to the corresponding, optionally in the 17-position by a lower alkyl or alkenyl radical substituted ^ j2 4i (io) _3. Alkoxy - 7α-methyl -17/9 - hydroxy - oestradienverbindungen reduces the 3-enol ether group by treatment with an acid under mild conditions to the desired zl ^{5 (10)} -3-keto-7a -methyl compound hydrolyzed and optionally introduces the substituents indicated in the 17-position before or after the hydrolysis of the 3-enol ether group.

The invention relates to new 7a-methyl steroids of the oestran series, of the general formula

where R is an oxygen atom or the group OX (aY) denotes, where X is a hydrogen atom or a phenylpropionyl radical and Y is a hydrogen atom or is a methyl, ethyl, vinyl or ethynyl radical and a process for their preparation.

WOrJnR _{1 is} a hydrocarbon _{radical, R 2 is} a hydrogen atom or an acyl radical and R _{3 is} a hydrogen atom or a lower alkyl or alkenyl radical to which

corresponding / l ² - ^{5 (10)} -3-alkoxy-7a-methyl-17 ^ -hydroxyoestradienverbindung which may optionally be further substituted by a lower alkyl or alkenyl radical, followed by the 3-Enoläthergruppe mild by treatment with an acid Loading

conditions hydrolyzed to the desired J ^{5 (1O)} -3-keto-17a-methyl compound, in which optionally before or after the hydrolysis of the 3-enol ether group, the substituents indicated in the 17-position can be introduced.

If the 17-alkylation takes place after the hydrolysis of the 3-enol ether group, the 3-keto group must be temporarily protected, e.g. B. by ketalization in the usual manner, for. B. by the reaction of the A ^5m - 3-keto steroid with an aliphatic alcohol and a weak acid. Another possibility is to prepare the ketalized zl ^{5 (10)} -3-ketosteroid by reacting the z) ^{2i5 (10)} -3-alkoxy compound obtained as an intermediate with an alcohol in the presence of an acidic catalyst.

The starting materials can already have a lower alkyl or alkenyl group in the 17-position, however this group can also be introduced at a later point in time.

The 3-ether group is usually a lower, aliphatic hydrocarbon radical, preferably one Methyl radical.

The reduction of the aromatic compound to the corresponding zl ^{2i5 <10)} -3-alkoxy compound is carried out by treating the first-mentioned steroid with an alkali metal in liquid ammonia and an alcohol. Lithium is preferably used.

The zi ^{2> 5 (10)} -3-alkoxy-oestradiene compound obtained in this way is then converted into the corresponding $ <^10> -3-keto compound by treatment with an acid under mild conditions.

For this hydrolysis one usually leaves oxalic acid together with an aqueous alcohol, e.g. B. Methanol, act for 20 to 60 minutes, but other weak acids, e.g. B. acetic acid, Propionic acid or butyric acid, can be used. As in the reduction of the aromatic Ring A reduces an optionally present 17-keto or 17-alkynyl group at the same time and one 17-ester group is split off reductively, the starting material is preferably a 17/3 hydroxysteroid or a 17β-hydroxy-17-alkyl or -17-alkenyl steroid.

After the reduction or, if necessary, at a later point in time, after the hydrolysis of the 3-enol ether group, the 17 / J-hydroxy group can be esterified and / or a 17-alkynyl group by oxidation the 17ß-hydroxy compound and then through-

introduced alkynylation and then optionally esterifying the 17/5-hydroxy-17a-alkynyl compound obtained. Instead of starting from a 17α-Α1-kyl or 17a-alkenyl compound, these groups can of course also be introduced at a later stage. In this case, a 17ß-hydroxy-steroid is used as the starting material, whereupon the _δ ιμιο) _ 3. Alkoxy - Ία - methyl - Yl β - hydroxy - steroid obtained as an intermediate product or the ^ "'- S-keto ^ a-methyl-n / S-hydroxy compound is oxidized and then subjected to the 17-alkylation reaction in the customary manner, whereupon the 17-hydroxy-17α-alkyl compound thus obtained is esterified if necessary.

The 17-hydroxyl group is oxidized in a manner known per se, e.g. B. by the Oppenauer process or with chromium trioxide. The alkylation in the 17-position can be carried out by adding a metal derivative of a corresponding saturated or unsaturated hydrocarbon to the 17-keto group of the compound in question. The metal \ derivative can be a Grignard compound, e.g. B. the magnesium bromide of the corresponding hydrocarbon or an alkyllithium compound. A special case of alkylation is the preparation of the 17-hydroxy-17-ethinyl compounds. For this purpose, the 17-ketosteroid is brought with acetylene in the presence of an alkali metal or an alkali metal compound, e.g. B. an alkali amide or alcoholates, for the reaction or stores a metal compound of acetylene, z. B. an alkali or alkaline earth compound to the 17-keto group of the starting material.

If necessary, in the end products in the 17-position present hydrocarbon radical can, for. B. be a methyl, ethyl, vinyl, ethynyl radical.

The secondary or tertiary 17-hydroxysteroids prepared by the above process can optionally be esterified. Phenylpropionic acid can be used for the esterification.

These esters can be prepared in a manner known per se by reacting the 17-hydroxysteroids with phenylpropionic acid or the anhydride or halide thereof.

The compounds which can be prepared according to the invention have very valuable biological properties. she exert androgenic, anabolic, oestrogenic gonad-inhibiting and ovulation-inhibiting effects out.

The compounds can be administered parenterally or orally in the form of suspensions, solutions, or emulsions solid pharmaceutical dosage units such as tablets, pills or coated tablets, usually after mixing with auxiliary substances or possibly other active ingredients, administered • the.

The invention is explained in more detail by means of the following examples.

example 1

60

A solution of 2 g of 7a-methyl-oestradiol-3-methyl ether in 60 ml of ether was added to 60 ml of liquid ammonia. Then 0.66 g were obtained at -60 ° C Lithium added.

After stirring for 30 minutes, 20 ml of absolute ethanol were carefully added dropwise. The ammonia was evaporated and the residue poured into water. After extraction with methylene dichloride, washing neutral with water and drying over sodium sulfate, the extract was evaporated to dryness under reduced pressure. After crystallizing from ether-hexane to give the 7a-methyl-3-methoxy-17/9-hydroxy-zJ ² - ^{5 (10)} -oestradien, [o] ₀ = + 72.7 ° (CHCl _3).

Ig la - methyl - 3 - methoxy - Π β - hydroxy _z] 2j (io). _estradiene J _n ioo _m i of methanol were 1.17 g of oxalic acid in 200 ml of distilled water. After stirring at 16 ° C. for 2.5 hours, 250 ml of distilled water were added. The crystal mass was filtered off with suction and washed neutral, the Δ ^{5 <10)} -3-keto-7α-methyl-17/3-hydroxy-estrene being obtained. Melting point 131 to 133 ° C; [a] _D = + 154 ° (CHCl ₃ ).

Esterification of this compound gave 17-acetate, 17-caproate, 17-capricate and that, respectively 17 / J-phenyl propionate.

Example 2

20 ml of toluene were distilled off from a solution of 10 g of 7a-methyl-17 / S-hydroxy-3-methoxy-zl ² ' ^{5 (10) -oestradiene in 450 ml of toluene.} Then 85 ml of cyclohexanone and 5 g of aluminum isopropoxide were added. After distillation for 2.5 hours, during which 50 ml of solvent were distilled off, the reaction mixture was cooled and a solution of 90 g of Seignette in 90 ml of water was added. It was distilled with steam, then the crystal mass was filtered off with suction, washed neutral, dried and chromatographed over silica gel, giving the 7α-methyl-17-keto-3-methoxy- Δ ² * ⁽¹⁰⁾ -estradien.

Acetylene was passed through a solution of 6 g of potassium in 50 ml of isopropanol and 90 ml of benzene for 3 hours. Then a solution of 12 g of 7a-methyl-17-keto-3-methoxy- _Z | 24ao). _{oestra (} jj _{en m} 50 ml of tetrahydrofuran and 60 ml of benzene were added and acetylene was passed in for a further 3 hours at 0 ° C.

The reaction mixture was kept at room temperature for one night and then 60 ml of ice water were added at 0 ° C. under nitrogen. The solvents were driven off by steam distillation, and the crude crystal mass was filtered off with suction, washed with water and dried. The residue was then dissolved in 60 ml of methanol and 7 g of oxalic acid in 120 ml of distilled water were added. After stirring for 2.5 hours at 16 ° C., 300 ml of water were added. After suctioning off, washing and drying, the crystal mass was chromatographed over silica gel, giving 7a-methyl-17a-ethynyl- Πβ -hydroxy-3-keto- Δ ^{5 <0)} -esters. Melting point 166 to 169 ° C; [a] ₀ = + 101 ° (CHCl ₃ ).

If the potassium acetylide was replaced by methyl magnesium bromide, the corresponding 17α-methyl compound was obtained. The physical data of the zJ ⁵ < ¹⁰ > -3-keto-7a, 17a-dimethyl-17/3-hydroxy-oestrene are: melting point 136 bis. 139 ° C; [a] _D = + 121 ° (CHCl ₃ ).

Example 3

A solution of 2 g of 7a-methyl-17a-äthinyl-1 Iß-hy droxy-3-keto-zJ ^{5 (10} '-oestren in 50 ml of ethyl acetate was 0.4 g of pre-hydrogenated, 5% palladium on barium sulfate in 10 ml Ethyl acetate added.

After the required amount of hydrogen had been taken up, the catalyst was filtered off and washed with ethyl acetate. After evaporation under reduced pressure it was chromatographed over silica gel, whereby the 7a-methyl-17a-ethyl-17 / f-hydroxy-3-keto-J ^{5 (} 10'-oestrene. Melting point 142 to 145 ⁰ C; [a ] ". = + 130 ° (CHCl ₃ ).

Esterification of this compound gave the 17 / J-phenylpropionate.

Was hydrogenation after ingestion of half the. interrupted the required amount of hydrogen, the z] ^{5 (10)} -3-keto-7a-methyl-17/3-hydroxy-17a-vinyl-estrene was obtained.

Example4

⁵ g /) 5 ( ¹⁰ > -3-keto-7a-methyl-17 /} - hydroxy-oestrene, prepared according to Example 1, were dissolved in 165 ml of acetone, this solution was cooled to 5 ° C. and 6.5 ml of a Solution of 8 n-chromic acid according to Jones was added with stirring. After stirring for 10 minutes, the acetone was distilled off, water was added and the resulting precipitate was filtered off, dried and crystallized from a mixture of methanol and water, whereby zl ^{5 (10)} -3, 17-diketo-7a-methyloestrene, melting point 111 to 113 ° C; [a] _o = + 235 ° (CHCl ₃ ).

connection
(1 week orally)

Test report

Table I.

connection
(1 week orally)

comparison

J ^{5 (10)} -3-keto-17/3-hydroxy-17a-ethereal 1-oestren

0.125 mg / d

0.25 mg / d

0.5 mg / d

1.0 mg / d

2.0 mg / d

4.0 mg / d

z) ^{5 (10)} -3-keto-7a-methyl-17/3-hydroxy-17a-ethhinyloestrene

0.125 mg / d

0.25 mg / d

Seeds Ventral ■ Mus- · bladder prostate culus (mg) (mg) (mg) 6.8 11.2 20.0 9.8 10.6 18.8 11.2 13.0 19.2 15.0 12.4 23.1 14.4 13.1 22.3 16.8 15.8 22.1 19.8 19.1 20.2 16.9 14.5 20.5 15.1 14.9 25.0

Levatpr Ani

25th

30 _Δ 5 <io> _3_Keto-7a-methyl-17/3-hydroxy-17a-ethhinyloestrene

0.5 mg / d

1.0 mg / d

2.0 mg / d

4.0 mg / d

17a-methyl-testosterone

0.125 mg / d

0.25 mg / d

0.5 mg / d

1.0 mg / d

2.0 mg / d

4.0 mg / d

17a-ethynyl-oestradiol

^ g / d

30 μg / d

60 μg / d

Seminal vesicle

(mg)

17.3
21.0
19.6
26.0

10.5
11.7
12.2
15.8
18.8
30.6

17.0
17.5
17.6
17.8

Ventral prostate

(mg )

20.0 28.5 27.0 28.5

30.9 33.1 48.7 51.2 59.2 72.0

13.4 12.4 10.5 10.7

Muscle

(mg)

28.7 34.8 33.1 35.7

27.0 26.6 27.2 28.1 34.1 38.6

22.1 19.6 19.1 18.6

Levator Ani

The anabolic and estrogenic effect of a substance is an important measure of its pharmacological behavior. To determine it, the A ^{5 m} - 3 - keto - 7α - methyl -1 7 β - hydroxy - 17α - äthinyl - oestren with the known ^ 5 (10). 3 _ K _eto - ^ _ hydroxy. γη _α . äthinyl-oestrien compared.

The corresponding values can be found in Table I below.

45 '

55

60

65 An increase in the weight of the seminal vesicle and the ventral prostate is regarded as a measure of the androgenic resp. androgenic / estrogenic effectiveness, while weight gain of the Levator Ani muscle for the Assessment of the anabolic effect is used.

The table shows that J ^{5 (10)} -3-keto-17a - methyl -17 /? - hydroxy -17a - äthinyl - oestren, as can be seen from the weight gain of the Levator Ani muscle, is a strongly anabolic compound , while the corresponding known 7-desmethyl compound is completely inactive in this regard at any dosage.

After comparing the anabolic properties of the 7a-methyl steroid of the invention with a well-known, highly anabolic compound, namely Ha-methyl-testosterone, apparently both work Connections practically equally strong.

In order to provide evidence that the influence of the 7a-methyl-oestrene according to the invention on the The weight of the levator ani muscle is not due to the estrogenic nature of this compound came, the results of a Levator Ani muscle test were included in the table above, which using a known, estrogenic compound, namely 17a-ethynyl-oestradiol performed would. It is clear from the table that these compounds add to the weight of the Levator Ani muscle in no way affect.

Estrogenic effect

The estrogenic effect was determined by the Allen-Doisy test determined. -

Table II

J ⁵ " ⁰⁾ -3-keto-l 7 /? - hydroxy- Vaginal smear /) ^{5 (10)} -3-keto-7a-methyl- Vaginal smear 17 α-ethinyl-estrene 0/8 positive 17 /? - hydroxy-17a-ethinyl-oestrene 0/8 positive dose
(μ $) 1/8 positive dose 0/8 positive 50 5/8 positive 50 5/8 positive 100 7/8 positive 100 200 200 400

The table shows that both the known connection and the new connection have practically the same strength as estrogen.

In summary, it can therefore be said that the zl ^{5 (10)} -3-keto-7a-methyl-17 / S-hydroxa-17a-äthinyloestren is an extremely valuable compound because of its anabolic and estrogenic properties. The combination of these properties is all the more surprising since the corresponding lower homologues, namely the 7-desmethyl compounds, have no anabolic effects at all.

In other respects, too, the properties of the 7a-methyl steroids according to the invention are completely different from those of the corresponding 7-desmethyl steroids, which can be seen, among other things, from the results of the comparative experiments between the known zl ^{5 (10)} -3-keto-17/3 -hydroxy-17a-methyl-oestren and the corresponding 7a-methylsteroid according to the invention were carried out.

The procedure was as follows: Adult female rats with regular 4-day Ostruscyclen was given twice a day Substance administered orally. The treatment began on the day of the ostrus and thus for a few hours after ovulation and lasted 5 days. An autopsy was done on the sixth day.

In the normal comparison animals one finds eggs without granular cells, which leads to the conclusion that that ovulation occurred 30 hours before.

Finding eggs with granular cells in steroid-treated rats is evidence that that ovulation was delayed by about 24 hours.

An inhibition of ovulation or a shift ovulation for at least 30 hours occurred in these rats without occurring on the sixth Day there were eggs in the fallopian tube.

Table III

Quantity normal ver
late inhibited connection the
Rats 6th 0 0 comparison 6th zl ^{5 (10)} -3-keto- 17 /? - hydroxy 17a-methyl-oestrene 6th 0 0 2 7i6 mg / day (oral) 6th zJ ^{5 (10} > -3-keto- 7a-methyl- 17 ^ i-hydroxy 17a-methyl-oestrene 2 3 0 2 V ₁₆ mg / day (oral) 5 J ^{5 (10)} -3-keto- 17 / S-hydroxy 17a-methyl-oestrene 4th 2 0 2 V ₄ mg / day (oral) 6th

connection Quantity
the
Rats normal ver
late inhibited 5
/) ⁵ < ¹⁰ > -3-keto-7a-methyl-
17/3 hydroxy
17a-methyl-oestrene
_io 2 ¹ A mg / day (oral) 6th 0 0 6th

From Table III, it is clear that the known compound when administered orally at a dose of ₁₆ mg twice a ¹ I ovulationshemmend not daily functions while the corresponding inventive 7a-methyl compound ovulation-inhibiting properties. When administered orally in a dose of V ₄ mg twice a day, the known compound has only a slight effect on ovulation-delaying, while the corresponding 7α-methyl compound according to the invention is completely ovulation-inhibiting.

Table IV

A = 4 ^{5 <10)} -3-keto-17a-vinyl-17 /? - hydroxy-oestren B = / l ^{S (lo} > -3-keto-7a-methyl-17a-vinyl-17.3-hydroxy- oestren

Allen Doisy test

dose

1.00 mg
0.50 mg

Vaginal smear
AWAY

1/8 positive
0/8 positive

7/8 positive
1/8 positive.

Plasma cholesterol test

dose

1.00 mg

Change in cholesterol levels
AWAY

-27%

-62%

The new compound B is at least twice more estrogenically active than the known compound A and has a cholesterol-lowering effect at least twice as strong.

It was also found that Zl ^{5 <10)} -3-keto-7a-methyl-17a-ethyl-17 / hydroxy-oestren in the Clauberg test (progestative effect) at a dose of 0.25 mg

(orally) is active, while Δ ^5α0) -3 - keto-17α-ethyl-17/3-hydroxy-oestren is inactive at this dose.

Other pharmacological effects of compounds according to the invention emerge from the following tables:

Allen-Doisy test (estrogenic effect

connection

zl ^{5 (10)} -3-keto-7a-methyl-17 / Ϊ-hydroxy-estrene
A ⁵ ^ 3K7h \

17 / Myydroxy-oestren-17 / Ϊ - phenylpropionate

dose
(orally)

1.00 mg

1.00 mg

Vaginal smear
Rats

6/8 positive

8/8 positive

409 608/202

MLA test (anabolic effects)

connection dose
(1 week) MLA comparison 20.0 17 / J-hydroxy-estrene. 0.25 mg / day / orally 24.2 1.00 mg / day / orally 33.1 zl ^{5 (10)} -3-keto-7a-methyl- 17 / i-hydroxy-oestren- 17 /? - phenyl propionate 0.25 mg / day / subc. 34.4 0.50 mg / day / subc. 38.5 1.00 mg / day / subc. 53.5 zl ^{5 (10)} -3-keto-7a-methyl- 1 la- vinyl-17β-hydroxy- oestren 1 00 me / Tae / oral 36.2 zl ⁵ < ^lo > -3-keto-7a-methyl- 17a-ethyl-l 7/3-hydroxy- oestren 0.125 mg / day / orally 25.1 0.25. mg / day / orally 26.5 0.50 mg / day / orally 37.6 1.00 mg / day / orally 33.4

The new compounds are therefore very effective anabolically.

Claims (1)

Patent claims: 1. 7α-methyl- Δ ^{5 (10)} -steroids of the general formula To produce these compounds, a compound is reduced by a method known per se the general formula OR ₂